Objective:. To test the effectiveness of the long-term administration of isotretinoin in reducing the occurrence of basal cell carcinoma (BCC) in patients with previously treated BCC and to measure the toxicity associated with this regimen. Background: High dose isotretinoin has been reported to have a prophylactic effect on nonmelanoma skin cancer, although it is associated with significant toxicity. Methods: A multicenter clinical trial was conducted at eight medical centers in the U.S. A total of 981 patients with two or more previously confirmed BCC were randomly assigned to receive either 10 mg of isotretinoin or placebo daily. Patients were followed for 36 months on intervention and were monitored at six month intervals. Progress: The active intervention phase of the trial ended in 1990. Results showed that after 36 months of intervention, no statistically significant treatment group differences in either the cumulative percent of patients with incident BCC or the annual rate of BCC formation were observed. Adverse effects, including axial skeletal changes, were higher in the isotretinoin treated group. This cohort of 981 men has also been used to examine the effect of baseline constitutional risk factors on the subsequent risk of basal cell carcinoma (BCC), squamous cell carcinoma of the skin (SCC), and actinic keratoses (AK). In multivariate analysis, male gender, age greater than 65 years, the number of previous BCCs, and history of SCC were predictive of all three study outcome measures. A manuscript documenting these results is in preparation. In addition, three nested case control studies using stored biologic specimens are in the planning stages. One study will examine (in collaboration with Fox Chase Cancer Center) the relation of prediagnostic levels of several serum carotenoids and subsequent risk of nonmelanoma skin cancer in the cohort. Another study will investigate the association between polymorphisms of certain DNA repair genes (specifically, XPD, XPF, XRCC1 and XRCC3), associated DNA repair capacity and the risk of subsequent nonmelanoma skin cancer. In addition, using tumor tissue DNA, we will examine loss of heterozygosity of the patched gene (chromosome 9q22) and its relation to superficial multicentric basal cell carcinoma and nodular basal cell carcinoma in non-sun exposed areas of the body.